title: Zinc inhibits osteoclast differentiation by suppression of Ca2+-Calcineurin-NFATc1 signaling pathway.
abstract: BACKGROUND
  Zinc, an essential trace element, inhibits osteoclast differentiation in vitro and in vivo. The molecular mechanism for the inhibitory effect of zinc, however, is poorly understood. The purpose of this study was to investigate the effect of zinc and determine its molecular mechanism on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in mouse bone marrow-derived monocyte cells (BMMs) and RAW264.7 cells.
  
  
  RESULTS
  In BMMs, zinc treatment during osteoclast differentiation decreased RANKL-induced osteoclast formation in a dose-dependent manner. We show that zinc suppressed the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Zinc also accumulated phospho-Nfatc1 (p-Nfatc1) in the cytosol in a dose-dependent manner and inhibited the translocation of Nfatc1 to the nucleus in RAW264.7 cells. Zinc suppressed the activities of Nfatc1 in the nucleus without changing the activities of NF-κB in RAW264.7 cells. In contrast, calcineurin activity decreased in response to zinc but its protein level was unchanged. RANKL-induced Ca2+ oscillations were inhibited by zinc treatment, but phospho-phospholipase Cγ1 (p-PLCγ1), the upstream signaling molecule of Ca2+ oscillations, was unaffected. Moreover, a constitutively active form of Nfatc1 obviously rescued suppression of osteoclastogenesis by zinc.
  
  
  CONCLUSIONS
  Taken together, these results demonstrate for the first time that the inhibitory effect of zinc during osteoclastogesis is caused by suppressing the Ca2+-Calcineurin-NFATc1 signaling pathway. Thus, zinc may be a useful therapeutic candidate for the prevention of bone loss caused by NFATc1 activation in osteoclasts.
authors.affiliation: Department of Microbiology, Yonsei University College of Medicine, Seoul, Republic of Korea. jaemyun@yuhs.ac.
authors.forename: Kwang Hwan
authors.initials: KH
authors.lastname: Park
authors.forename: Boryung
authors.initials: B
authors.lastname: Park
authors.forename: Dong Suk
authors.initials: DS
authors.lastname: Yoon
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Kwon
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D019703:Calcineurin; D015032:Zinc; D002118:Calcium